Abstract A growing number of human epidemiological studies link childhood asthma to prenatal environmental exposures, with particular emphasis placed on exposures to cigarette smoke and diesel exhaust. Human association studies are supported by emerging mouse models that provide evidence of causality. In the parent R01HL122995 we describe one of these models and propose to use it to study mechanisms. We hypothesize that in utero exposure to diesel exhaust particles (DEP) promotes asthma susceptibility through aryl hydrocarbon receptor (AhR)-dependent priming of natural killer (NK) cells. AhR is a transcriptional factor that is activated by DEP-derived polycyclic aromatic hydrocarbons (PAH). In R01HL122995 we link PAH and AhR to induction of type-2/3 cytokines in offspring NK cells. In the Administrative Supplement we would like to go one step further and propose to block this pathway through supplementation of maternal diet with nicotinamide riboside (NR). NR is a naturally-occurring compound that is biochemically related to niacin (vitamin B3). NR and niacin are precursors of nicotinamide adenine dinucleotide (NAD+). NR is considered superior to niacin because it is more potent in raising NAD+ and devoid of niacin side effects. NAD+, the end product of niacin/NR transformations, is an important coenzyme and cosubstrate that drives many fundamental cellular processes, including ATP generation, DNA repair, mitochondrial maintenance and protection from cell death. The rationale to use a NAD+-boosting compound as an antidote for PAH/DEP in our model comes from studies showing that 1) PAH and AhR deplete NAD+, 2) NAD+ depletion significantly contributes to effects of PAH and AhR, 3) Maintenance of normal NAD+ levels is important in prevention of inflammation, which is consistent with the homeostatic role of NAD+. NAD+ is an essential and rate-limiting cosubstrate of sirtuin enzymes. When NAD+ levels are normal, sirtuins deacetylate and, thereby, inactivate GATA3 and NF-?B, precluding transcription of type-2/3 cytokine genes. If NAD+ levels decline, rates of sirtuin-catalyzed reactions decrease. Sirtuin inactivation results in acetylation and activation of GATA3 and NF-?B, leading to cytokine production. Described studies collectively imply that NAD+ depletion and sirtuin inactivation are important mechanisms linking PAH/AhR with transcription of type-2/3 immunity genes. We hypothesize that maternal intake of the NAD+ precursor NR will reverse DEP-induced and AhR-mediated type-2/3 re-programming of offspring NK cells and, therefore, block transgenerational transmission of asthma susceptibility. The Specific Aim of the Administrative Supplement is to test the effectiveness of maternal NR intake in prevention of DEP- mediated NK cell activation and induction of asthma predisposition in offspring. To address this Aim, we plan to administer NR to DEP-exposed mothers and examine development of asthma predisposition in offspring. We will also measure type-2/3 cytokine production by offspring NK cells. Finally, we will measure NAD+, activity of sirtuins and acetylation of NF-?B and GATA3 in these cells.